The present invention relates to a process for producing 2′-deoxy-2′-fluorouridine, which is an important intermediate of medicines.
The target of the present invention, 2′-deoxy-2′-fluorouridine, is an important intermediate of medicines. Conventional production processes can be divided into the following two, and representative publications are cited.
(1) A process of conducting a ring opening and fluorination of 2,2′-anhydrouridine with hydrofluoric acid (see Non-patent Publication 1 (J. Org. Chem. (USA), 1964, Vol. 29, No. 3, pp. 558-564)).
(2) 1-β-D-Arabinofuranosyluracil in 3′,5′-hydroxyl-protected form is dehydroxyfluorinated by DAST ((C2H5)2NSF3) (see Non-patent Publication 2 (Chem. Pharm. Bull. (Japan), 1994, Vol. 42, No. 3, pp. 595-598)).
As a technology related to the present invention, in syntheses of 2′-deoxy-2′-fluoroadenosine and 2′-deoxy-2′-fluoroguanosine, there are disclosed processes in which corresponding 9-β-D-arabinofuranosyladenine in 3′,5′-hydroxyl-protected form and N2-isobutyryl-9-β-D-arabinofuranosylguanine in 3′,5′-hydroxyl-protected form are reacted with trifluoromethanesulfonyl chloride in the presence of sodium hydroxide to respectively convert them to corresponding 2′-triflates, followed by reactions with tetrabutylammonium fluoride (TBAF) (see Non-patent Publication 3 (Tetrahedron Lett. (Great Britain), 1977, Vol. 18, No. 15, pp. 1291-1294), Non-patent Publication 4 (Chem. Pharm. Bull. (Japan), 1981, Vol. 29, No. 4, pp. 1034-1038), Non-patent Publication 5 (J. Carbohyd. Nucl. Nucl. (Great Britain), 1980, Vol. 7, No. 2, pp. 131-140), Non-patent Publication 6 (Chem. Pharm. Bull. (Japan), 1981, Vol. 29, No. 11, pp. 3281-3285)).
The process for producing 2′-deoxy-2′-fluorouridine, which is disclosed in Non-patent Publication 1, was much limited in material of the reactor, since the reaction was conducted by using an excessive amount of hydrofluoric acid, which is highly corrosive, under high temperature. The productivity was inferior since the substrate was diluted with reaction solvent to high degree, and the reaction yield itself was low. From the industrial viewpoint, it was difficult to say that the process is an industrial production process, since it uses hydrofluoric acid that is difficult in handling in large amount, and since column chromatography is necessary for purifying the obtained product.
On the other hand, in the production process of non-patent publication 2, it is necessary to use a special fluorination agent that is industrially expensive and problematic in handling in large amount, and the reaction yield is also ordinary. Thus, it was difficult to say that the process is an industrial production process.
The processes for synthesizing 2′-deoxy-2′-fluoroadenosine or 2′-deoxy-2′-fluoroguanosine, which are disclosed in Non-patent Publications 3-6, gave the target with only very low yield.
The reaction of obtaining 2′-deoxy-2′-fluoroadenosine or 2′-deoxy-2′-fluoroguanosine by fluorinating a 2′-triflate form, which is disclosed in Non-patent Publications 3-6, is considered to be a nucleophilic SN2 substitution reaction by fluorine anion (F−). In this reaction, “an elimination reaction of a triflate group (CF3SO3− group)” occurs competitively as a side reaction, and there is produced as a by-product a compound in which 1′-position carbon and 2′-position carbon are bonded by a double bond. The cause of low yield in the Non-patent Publication 3 is also due to this side reaction. This is an essential problem inherent in the nucleophilic SN2 substitution reaction by fluorine anion (F−). A similar problem arises in the production of the present invention's target compound 2′-deoxy-2′-fluorouridine, too.
Thus, there was a strong desire for a process of industrially advantageously producing 2′-deoxy-2′-fluorouridine.
Furthermore, since 2′-deoxy-2′-fluorouridine, the final target compound in the present invention, is a water-soluble and scarcely crystalline compound, it was necessary to conduct a purification by column chromatography to purify it as a high-purity, white-color, crystalline powder with high recovery (Non-patent Publication 1 and Non-patent Publication 2). Thus, it placed a burden in purification procedure. There has been no report yet of a process capable of purifying it in the form of a high-purity, white-color, crystalline powder with high recovery by a simple purification procedure like recrystallization purification. Thus, there was also a strong desire for an industrial purification process of 2′-deoxy-2′-fluorouridine.